1. Field of the Invention
The present application relates to process of making atazanavir sulfate, in particular process of making crystalline Form A of atazanavir sulfate.
2. Description of the Related Art
Atazanavir sulfate is an azapeptide inhibitor of HIV-1 protease. It is currently marketed under the trade name REYATAZ® and indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. The chemical name for atazanavir sulfate is (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1). Its molecular formula is C38H52N6O7.H2SO4, which corresponds to a molecular weight of 802.9 (sulfuric acid salt). The free base molecular weight is 704.9. Atazanavir sulfate has the following structural formula:

U.S. Pat. No. 6,087,383 discloses a process of making atazanavir sulfate in Form A (which is referred to as Type I crystals in Example 3 of U.S. Pat. No. 6,087,383). The process comprises dissolving atazanavir base in a mixture of acetone and 5 M sulfuric acid aqueous solution at 50° C. followed by seeding with Form A of atazanavir sulfate crystals.
U.S. Pat. No. 7,829,720 also discloses a process of making atazanavir sulfate in Form A. The process comprises dissolving atazanavir base in a mixture of concentrated sulfuric acid, acetone, and N-methylpyrrolidone (NMP). After the mixture is seeded with Form A of atazanavir sulfate crystals, the resulting atazanavir sulfate in Form A is then obtained.
The two processes respectively disclosed in U.S. Pat. Nos. 6,087,383 and 7,829,720 use acetone along with sulfuric acid to prepare atazanavir sulfate in Form A. Mesityl oxide (4-methyl-3-penten-2-one), a potential genotoxic impurity (PGI), is very likely to be formed in the processes disclosed in U.S. Pat. Nos. 6,087,383 and 7,829,720. An extremely accurate analytical method is required to monitor content of the undesired mesityl oxide impurity in a final atazanavir sulfate product.
Xu et al, Organic Process R & D 2002, 6, 323 also discloses a process of preparing atazanavir sulfate in Form A. The process comprises dissolving atazanavir base in a mixture of EtOH and concentrated sulfuric acid. The resulting mixture is treated with n-heptane to facilitate precipitation of atazanavir sulfate in Form A. n-Heptane comprises many small amounts of side products. Many residual solvent impurities are detected in final atazanavir sulfate product via head space GC.
Therefore, there is still a need for an improved process of making atazanavir sulfate in Form A.